The use of chemotherapy and radiotherapy to treat cancer patients is associated with severe side-effects due to the toxicity of such treatments to normal cells, particularly epithelial cell populations, including stem cells, within the hair follicle, skin epidermis, and gastrointestinal mucosa.
Currently, there are few, if any, treatments to prevent cancer therapy side-effects. The full utility of chemotherapeutic drugs and radiation therapy (also referred to herein as “radiotherapy”) in the treatment of cancer has not been fully exploited due to adverse effects associated with the nonspecific cytotoxicity of these agents.
Effective treatments would preferably include: i) a means to decrease the concentration of systemically administered cytotoxic drugs in at-risk stem cells of the skin epidermis, hair follicles and gastrointestinal mucosa, and ii) a means to transiently decrease the concentration of oxygen in at-risk stem cells of the skin epidermis, hair follicles and gastrointestinal mucosa, because the majority of radiation-induced cell kill in tissue results from radiation-induced oxygen free radicals.
The toxicity of cancer therapy for epithelial cells accounts for many of the side-effects commonly suffered by persons undergoing a regimen of chemotherapy or radiotherapy. These include gastrointestinal distress, nausea, vomiting, diarrhea, proctitis, loss of appetite, hair loss, bone marrow suppression and skin rash or ulceration at the site of irradiation. These complications can be so difficult to endure that patients may forego or discontinue recommended cancer therapy treatments in order to avoid the side-effects. Typically, during the course of chemotherapy, the chemotherapeutic agent is administered in sub-optimal doses in order to minimize toxicity and to protect normal, drug-sensitive cells.
For example, gastrointestinal disturbances may compromise a patient's chances of recovery because they make it difficult for the patient to obtain the nourishment necessary to optimize their ability to fight disease. It appears that chemo- and radiotherapy-associated death and sloughing of gastrointestinal lumenal cells results in release into the vasculature of molecules associated with gastrointestinal damage. These blood-borne molecules, when detected by sites within the brain, trigger a nausea response that is so common among patients receiving chemotherapy. Present treatments with drugs, such as Ondansetron, serve to suppress these brain centers and thus, diminish the nausea response. However, the primary destruction of the gastrointestinal lining still limits the most effective use of chemotherapy.
A better mechanism to diminish nausea in these patients would be to eliminate the primary destruction of the gastrointestinal surface and thereby prevent the release of damage-associated, nausea-inducing molecules, rather than just suppressing the effects of these molecules in the brain. Reducing the sensitivity of normal cells to chemotherapeutic agents would allow the administration of higher drug dosages and render the chemotherapy more effective.
Radiation-induced dermatitis is another recognized side effect of cancer treatment. Radiotherapy is used regularly as a primary or adjunct therapy for cancer patients, but dermatitis or scorched skin within the irradiated field is a common and painful side effect in the majority of radiation therapy patients
Mucositis is an also important and costly side-effect of cancer therapy. As an inflammation of a mucosal surface, mucositis is a frequent, potentially severe complication of chemotherapy and/or radiotherapy. It can manifest as erythema, desquamation, ulcer formation, bleeding and exudate. It is generally accepted that mucositis results from the direct inhibitory effects of chemotherapy or radiotherapy on DNA replication and mucosal stem cell proliferation. These events result in reduction in the regeneration capability of the basal epithelium, leading to mucosal atrophy, collagen breakdown, and ulceration. A secondary effect is infection from a number of pathogens after the breakdown of the protective mucosal barrier.
Mucositis can be present throughout the gastrointestinal and urogenital tract, from the oral cavity to the intestines and rectum. It is particularly debilitating because it can lead to abnormal nutrition, increased systemic infections, use of narcotics to diminish pain, and postponement of cancer therapy. No commercial drugs are known to prevent mucositis due to cancer therapy. Present treatments for oral mucositis include application of basic principles of oral hygiene, and therapies, such as topical anesthetics and systemic analgesics to relieve pain, are used in an effort to minimize the symptoms. Auxiliary measures to protect normal cells of the gastrointestinal tract involve nutrient stimulation and maximizing the intake of growth factors. However, those therapies also do not address the underlying cause of mucositis.
The successful implementation of protective therapies that promote routine growth and proliferation of normal cells in the presence of radiotherapy or chemotherapeutic agents will permit the use of higher dose, more aggressive cancer therapy. Consequently, these protective therapies may not only address the side-effects of cancer and its treatment, but may enable greater treatment efficacy against cancer than is seen using current therapies.
Two useful targets for development of protective therapies are (1) epithelial cells, such as those lining the oral and entire gastrointestinal or urogenital tract, and (2) other epithelial cells, for example those of the skin, including hair follicles and the epidermis. The effectiveness and utility of existing approaches is limited, underscoring the requirement for new effective therapies to alleviate these side-effects.
There is, therefore, need for safe and effective drug preparations that can reduce the side-effects of cancer treatment, for example mucositis, and methods for reducing or minimizing these side-effects. More specifically, there exists a need to provide methods for topical administration of a vasoconstrictor to at-risk, non-neoplastic tissues, and by so doing, reduce delivery of systemic chemotherapy and cause transient hypoxia to reduce oxygen free-radical formation during radiation therapy
There is also a need to provide topical vasoconstrictor preparations, which by design as to dose, delivery vehicle formulation, and vasoconstrictor receptor specificity, provide protection, especially local protection, to at-risk, non-neoplastic cells against cancer therapy side-effects, but reduce or even prevent one or more unwanted systemic effects of the applied vasoconstrictor.
There is also a need to provide preparations that enable topical, oral administration of a vasoconstrictor in a formulation whose flavor is well tolerated by cancer patients.
There is also a need for methods of treatment that comprise the application of an effective but non-toxic dose of vasoconstrictor combined with topical delivery vehicles that facilitate delivery to the skin or mucosal surfaces of a human or animal cancer patient.